Bioactivation and reactivity research advances-2023 year in review.

Advances in the field of bioactivation have significantly contributed to our understanding and prediction of drug-induced liver injury (DILI). It has been established that many adverse drug reactions, including DILI, are associated with the formation and reactivity of metabolites. Modern methods allow us to detect and characterize these reactive metabolites in earlier stages of drug development, which helps anticipate and circumvent the potential for DILI. Improved in silico models and experimental techniques that better reflect in vivo environments are enhancing predictive capabilities for DILI risk. Further, studies on the mechanisms of bioactivation, including enzyme interactions and the role of individual genetic differences, have provided valuable insights for drug optimizations. Cumulatively, this progress is continually refining our approaches to drug safety evaluation and personalized medicine.Shuai Wang and Cyrus Khojasteh, on behalf of the authors.

Thyroidectomy in children and adolescents: a systematic review.

Background: Thyroid surgery in pediatric population is not as common as that in adults, although they share the same indications, techniques and complications. This review aims to evaluate the surgical management of thyroid disease in patients under 18 years old. Methods: We conducted a bibliographic search in the international literature. Data from the identified studies such as demographics, indication for surgery, type of procedure, complications and length of hospital stay were recorded. A retrospective review study of all patients under 18 years old who underwent thyroidectomy was performed. Results: We included 37 retrospective studies and a total of 12,728 patients. Thyroidectomy was more common in female patients and the mean age was approximately 14 years old. The leading indication for surgery was benign thyroid pathology. Due to the surgical treatments' safety and effectiveness in young patients, total and subtotal thyroidectomy, whether for malignancies or benign diseases, is becoming more popular today. The most often occurring complication of pediatric thyroid surgery is hypoparathyroidism. Despite the high likelihood of recurrence of pediatric malignancies, overall survival rates of pediatric thyroid cancer are excellent. Conclusions: Thyroidectomy performed by high-volume thyroid surgeons in children and adolescents is considered an efficient and safe method of treatment of thyroid disease.

Digital Training for Nurses and Midwives to Improve Treatment for Women with Postpartum Depression and Protect Neonates: A Dynamic Bibliometric Review Analysis.

The high prevalence of postpartum depression makes it necessary for midwives and nurses to implement prenatal interventions for expectant mothers. The current study aims to investigate and highlight the importance of the digital training of nurses in order to help women mitigate the symptoms of postpartum depression and protect infants. To approach this, we conducted a bibliometric analysis to address the study's main objective. Articles were retrieved from the Scopus database for the timeframe 2000-2023. Data analysis was conducted using the statistical programming language R (version R-4.4.) and the bibliometric software VOSviewer (version 1.6.20) and Biblioshiny (version 4.1.4), focused on year, journal, and country. For this investigation, we selected a total of 31 MeSH keywords and sub-headings that exhibited significant frequencies. We consistently used six significant clusters of MeSH keywords. We obtained a total of 585 articles from the Scopus database that were major contributors to the field of PPD, as evidenced by their extensive publication of research articles and their influential role in the domain. The studies included a thorough analysis of depression research, the use of scales for diagnosing and screening PPD, psychological studies related to PPD, and the exploration of causes, mechanisms, outcomes, and genetic factors. Our study's results demonstrate a steady and significant increase in the availability of information on PPD. Importantly, the novelty of the current study lies in highlighting the need for a transition in the ways in which nurses and midwives are trained to mitigate postpartum disease by integrating emerging technologies into their practices. The knowledge provided here has the potential to serve as a foundation for future advancements in obstetric psychology, both presently and in the future.

The Potential Impact of the Gut Microbiota on Neonatal Brain Development and Adverse Health Outcomes.

Over the past decade, microbiome research has significantly expanded in both scope and volume, leading to the development of new models and treatments targeting the gut-brain axis to mitigate the effects of various disorders. Related research suggests that interventions during the critical period from birth to three years old may yield the greatest benefits. Investigating the substantial link between the gut and brain during this crucial developmental phase raises fundamental issues about the role of microorganisms in human health and brain development. This underscores the importance of focusing on the prevention rather than the treatment of neurodevelopmental and neuropsychiatric disorders. The present review examines the gut microbiota from birth to age 3, with a particular focus on its potential relationship with neurodevelopment. This review emphasizes the immunological mechanisms underlying this relationship. Additionally, the study investigates the impact of the microbiome on cognitive development and neurobehavioral issues such as anxiety and autism. Importantly, it highlights the need to integrate mechanistic studies of animal models with epidemiological research across diverse cultures to better understand the role of a healthy microbiome in early life and the implications of dysbiosis. Furthermore, this review summarizes factors contributing to the transmission of gut microbiome-targeted therapies and their effects on neurodevelopment. Recent studies on environmental toxins known to impact neurodevelopment are also reviewed, exploring whether the microbiota may mitigate or modulate these effects.

Risk of Major Adverse Cardiovascular Events and Venous Thromboembolism with JAK Inhibitors versus TNF Inhibitors in Rheumatoid Arthritis Patients: A Systematic Review and Meta-Analysis.

Objective: The aim of this study was to compare the risk of major cardiovascular events (MACE) and venous thromboembolic events (VTE) between tumour necrosis factor (TNF) and Janus kinase (JAK) inhibitors in patients with rheumatoid arthritis (RA). Methods: We researched PubMed, Scopus, Cochrane Library, and clinicaltrials.gov until December of 2023 for randomised controlled trials (RCTs) and observational studies. The outcomes studied were MACE (stroke, heart attack, myocardial infarction, sudden cardiac death) and VTE (deep vein thrombosis, pulmonary embolism). We pooled data using random effects model. Risk for the reported outcomes was expressed as odds ratio (OR) with a 95% confidential interval (CI). We performed a subgroup analysis based on study design. Results: We identified 23 studies, 20 of which compared the odds for MACE and 14 the odds for VTE between JAK and TNF inhibitors in RA patients. Ten studies were RCTs and the rest were observational. Regarding MACE risk we pooled data from a total of 215,278 patients (52,243 were treated with JAK inhibitors, while the rest 163,035 were under TNF inhibitors). Compared with TNF inhibitors, the OR for JAK inhibitors in regards with MACE risk was 0.87 (0.64-1.17, p<0.01). Regarding VTE, a total of 176,951 patients were analysed (41,375 JAK inhibitors users and 135,576 TNF inhibitors users). The OR for VTE for JAK inhibitors compared with TNF inhibitors was 1.28 (0.89-1.84, p<0.01). Conclusion: According to our results, there is no statistically significant difference for MACE or VTE in RA patients who receive either JAK or TNF inhibitors.

Focus on Filgotinib in Rheumatoid Arthritis: A Trial-Based Review.

Janus kinases (JAK)/Signal Transducer and Activator of Transcription (STAT) pathway is involved in pathophysiologic cascade of a notable number of rheumatic diseases. The development of JAK inhibitors has expanded treatment choices in rheumatoid arthritis (RA) with a sustained class-effect efficacy. Filgotinib is a novel selective inhibitor of JAK1 isoform licensed for use in RA and ulcerative colitis. In this review we aim to present an analysis of filgotinib's efficacy and drug-specific safety warnings. Patients with RA with or without concomitant conventional synthetic Disease-Modifying Antirheumatic Drugs (csDMARDs) (naïve or experienced) and those who have failed biologic Disease-Modifying Antirheumatic Drugs (bDMARDs) were examined in randomised clinical trials. Filgotinib was also tested against placebo, methotrexate, or adalimumab. Long-term extension trials provide insights for up to four years of continuous filgotinib administration. Beneficial effects are depicted in both disease activity parameters and quality of life indexes in moderate or severe RA with a longitudinal efficacy. In head-to-head comparison with adalimumab, filgotinib 200 mg was non-inferior. Adverse effects alerts are marked by the elevated risk of infectious adverse effects with the exception of herpes zoster infection, which has a low incidence.

The Role of Helicobacter pylori and Metabolic Syndrome-Related Mast Cell Activation Pathologies and Their Potential Impact on Pregnancy and Neonatal Outcomes.

Helicobacter pylori infection, a significant global burden beyond the gastrointestinal tract, has long been implicated in various systemic pathologies. Rising evidence suggests that the bacterium's intricate relationship with the immune system and its potential to induce chronic inflammation impact diverse pathophysiological processes in pregnant women that may in turn affect the incidence of several adverse pregnancy and neonate outcomes. Helicobacter pylori infection, which has been linked to metabolic syndrome and other disorders by provoking pericyte dysfunction, hyperhomocysteinemia, galectin-3, atrial fibrillation, gut dysbiosis, and mast cell activation pathologies, may also contribute to adverse pregnancy and neonatal outcomes. Together with increasing our biological understanding of the individual and collective involvement of Helicobacter pylori infection-related metabolic syndrome and concurrent activation of mast cells in maternal, fetus, and neonatal health outcomes, the present narrative review may foster related research endeavors to offer novel therapeutic approaches and informed clinical practice interventions to mitigate relevant risks of this critical topic among pregnant women and their offspring.

Bioisoteres for carboxylic acids: From ionized isosteres to novel unionized replacements.

Carboxylic acids are key pharmacophoric elements in many molecules. They can be seen as a problem by some, due to perceived permeability challenges, potential for high plasma protein binding and the risk of forming reactive metabolites due to acyl-glucuronidation. By others they are viewed more favorably as they can decrease lipophilicity by adding an ionizable center which can be beneficial for solubility, and can add enthalpic interactions with the target protein. However, there are many instances where the replacement of a carboxylic acid with a bioisosteric group is required. This has led to the development of a number of ionizable groups which sufficiently mimic the carboxylic acid functionality whilst improving, for example, the metabolic profile of the molecule in question. An alternative strategy involves replacement of the carboxylate by neutral functional groups. This review initially details carefully selected examples whereby tetrazoles, acyl sulfonamides or isoxazolols have been beneficially utilized as carboxylic acid bioisosteres altering physicohemical properties, interactions with the target and metabolism and/or pharmacokinetics, before delving further into the binding mode of carboxylic acid derivatives with their target proteins. This analysis highlights new ways to consider the replacement of carboxylic acids by neutral bioisosteric groups which either rely on hydrogen bonds or cation-π interactions. It should serve as a useful guide for scientists working in drug discovery.

Displaced Distal Fibular Epiphysis in a Child: A Clinical and Radiological Evaluation of a Rare Injury Hidden From the Initial Radiological Examination.

Fractures of the lateral malleolus are common in children. Isolated lesions of the distal fibula physis commonly comprise nondisplaced or minimally displaced fractures. An isolated, completely displaced epiphysiolisthesis of the distal fibula is an extremely rare lesion. This study introduces the case of an 11-year-old boy presenting an extremely rare lesion of an isolated, completely displaced distal fibular epiphysis that was difficult to diagnose on X-ray. Initial radiographic examination of the injured ankle showed normal configuration of the tibia and fibula on AP projection, with soft tissue swelling of the lateral malleolus. On the lateral projection, the talus completely covered the distal fibular epiphysis, and particular attention was required to reveal the complete displacement of the distal fibular epiphysis. A CT scan confirmed the diagnosis of an isolated, completely displaced distal fibular epiphysiolisthesis. The patient was treated with a closed reduction and made an uneventful recovery. This report highlights the importance of accurate clinical and radiological assessment of an isolated, completely displaced, distal fibular epiphysiolisthesis.

Placental and Renal Pathways Underlying Pre-Eclampsia.

Pre-eclampsia is a serious complication of pregnancy characterized by a state of multiorgan hypertensive disorders, with or without proteinuria and possible multiorgan dysfunction. Chronic kidney disease is an established risk factor for the development of pre-eclampsia, as angiogenic homeostasis is altered and the maternal circulation is already hypertensive. Facing pre-eclampsia in the context of chronic kidney disease is a challenging emergency for both the mother and the fetus. The clinical features and the management of this multi-organ disorder are clearly defined in the modern literature but the underlying pathophysiologic mechanisms remain not fully elucidated. Understanding the pathophysiology that mediates the onset of pre-eclampsia itself and in synergy with chronic kidney disease is fundamental for developing prompt prevention strategies, treatment planning, and patient counseling. This review aims to summarize the main molecular mechanisms involved in the process of pre-eclampsia, with a particular focus on the role of the kidneys and hormonal pathways related to renal function in normal pregnancy and pre-eclamptic syndromes.

Impact of Helicobacter pylori and metabolic syndrome on mast cell activation-related pathophysiology and neurodegeneration.

Both Helicobacter pylori (H. pylori) infection and metabolic syndrome (MetS) are highly prevalent worldwide. The emergence of relevant research suggesting a pathogenic linkage between H. pylori infection and MetS-related cardio-cerebrovascular diseases and neurodegenerative disorders, particularly through mechanisms involving brain pericyte deficiency, hyperhomocysteinemia, hyperfibrinogenemia, elevated lipoprotein-a, galectin-3 overexpression, atrial fibrillation, and gut dysbiosis, has raised stimulating questions regarding their pathophysiology and its translational implications for clinicians. An additional stimulating aspect refers to H. pylori and MetS-related activation of innate immune cells, mast cells (MC), which is an important, often early, event in systemic inflammatory pathologies and related brain disorders. Synoptically, MC degranulation may play a role in the pathogenesis of H. pylori and MetS-related obesity, adipokine effects, dyslipidemia, diabetes mellitus, insulin resistance, arterial hypertension, vascular dysfunction and arterial stiffness, an early indicator of atherosclerosis associated with cardio-cerebrovascular and neurodegenerative disorders. Meningeal MC can be activated by triggers including stress and toxins resulting in vascular changes and neurodegeneration. Likewise, H.pylori and MetS-related MC activation is linked with: (a) vasculitis and thromboembolic events that increase the risk of cardio-cerebrovascular and neurodegenerative disorders, and (b) gut dysbiosis-associated neurodegeneration, whereas modulation of gut microbiota and MC activation may promote neuroprotection. This narrative review investigates the intricate relationship between H. pylori infection, MetS, MC activation, and their collective impact on pathophysiological processes linked to neurodegeneration. Through a comprehensive search of current literature, we elucidate the mechanisms through which H. pylori and MetS contribute to MC activation, subsequently triggering cascades of inflammatory responses. This highlights the role of MC as key mediators in the pathogenesis of cardio-cerebrovascular and neurodegenerative disorders, emphasizing their involvement in neuroinflammation, vascular dysfunction and, ultimately, neuronal damage. Although further research is warranted, we provide a novel perspective on the pathophysiology and management of brain disorders by exploring potential therapeutic strategies targeting H. pylori eradication, MetS management, and modulation of MC to mitigate neurodegeneration risk while promoting neuroprotection.

Post-Traumatic Stress Disorder Symptoms among Pediatric Healthcare Workers.

Post-traumatic stress disorder symptoms related to work in pediatric departments aremajor public health problems, as they directly affect health organizations, healthcare workers, and, due to the poor quality of care, the patients as well. The post-traumatic symptoms that a healthcare worker may experience are related to intrusion, avoidance, negative changes in cognition and mood, and changes in arousal and reactivity. The aim of the present investigation was to identify risk factors that contribute to the development of PTSD in pediatric healthcare workers, in order to implement necessary workplace measures. A sample of four hundred and forty-five pediatric workers at seven Greek public hospitals consented to participate in the survey. Socio-demographic data and a post-traumatic checklist (5th edition) were used to diagnose post-traumatic stress disorder. According to the results, risk factors for the development of post-traumatic symptoms include medical or nursing errors, threats to a child's life, and incidents of workplace bullying. More specifically, 25.2% of the participants had a provisional PTSD diagnosis, 72.8%of the sample experienced an incident involving a medical or nursing error in their workplace related to the treatment or care of a child, 56% experienced an incident involving a child's death or a threat to a child's life due to a serious illness or injury, and 55.5% experienced an incident of workplace bullying. In addition, it was found that having a university-level education, master's, or PhD, working in a circular shift, being assigned to a department by management rather than the worker, and dissatisfaction with salary were associated with post-traumatic stress disorder. The high rates of PTSD symptoms among participants highlight the need for prevention and management measures to protect and support the mental health of workers in pediatric departments. We propose frequent evaluations of the mental health of employees, more time for rest, incentives for professional development, utilization of their specializations and specialties, support from mental health specialists when symptoms are diagnosed, and the option for employees to change departments if they wish or if they show symptoms of mental trauma.

The Involvement of Neonatal Intensive Care Unit and Other Perinatal Factors in Postpartum PTSD After Cesarean Section.

BACKGROUND: The experience of a neonate hospitalised in the Neonatal Intensive Care Unit (NICU) is an understandably traumatic experience for the parents, especially, for the mothers of neonates. This mental distress resulting from preterm birth and/or NICU hospitalisation can be understood as post-traumatic symptomatology, according to the Diagnostic and Statistical Manual-5 version. The aim of this study is to investigate the impact of the admission of a neonate to the NICU (from any reason) on the development of postpartum post-traumatic stress disorder (PTSD) in a sample of women after cesarean sections. MATERIAL AND METHODS: A total of 469 women who gave birth with cesarean section from July 2019 to June 2020 participated in this study, from the original sample of 490 women who consented to participate. Data were obtained from the researcher's socio-demographic questionnaire, the past traumatic Life Events Checklist, the perinatal stressor Criterion A, and the Post-Traumatic Stress Checklist from the Diagnostic and Statistical Manual-5 version. RESULTS: A percentage of 46.64% of sample experienced postpartum PTSD. Factors associated with PTSD were placenta previa type4, abruption, bleeding (ß = .07, p = .049), premature contractions (ß = .08, p = .039), heavy medical history or previous gynecological history and preeclampsia (ß = .08, p = .034), abnormal heart rate, premature rupture of membrane, premature contractions, infections (ß = .14, p = .004), life of child in danger (ß = .12, p = .025), complications involving child (ß = .15, p = .002), complications involving both (child and mother) (ß = .12, p = .011), traumatic cesarean section (ß = .041, p < .001) and prematurity (ß = .12, p = .022). CONCLUSIONS: Additional measures must be taken for mothers of children who have been admitted to the NICU with psychological support interventions and reassessment of their mental state.

Potential impact of trained innate immunity on the pathophysiology of metabolic dysfunction-associated fatty liver disease.

Metabolic dysfunction-associated fatty liver disease (MAFLD) occurs in a low-grade inflammatory milieu dependent on highly complex networks that span well-beyond the hepatic tissue injury. Dysfunctional systemic metabolism that characterizes the disease, is further induced in response to environmental cues that modify energy and metabolic cellular demands, thereby altering the availability of specific substrates that profoundly regulate, through epigenetic mechanisms, the phenotypic heterogeneity of immune cells and influence hematopoietic stem cell differentiation fate. This immuno-metabolic signaling drives the initiation of downstream effector pathways and results in the decompensation of hepatic homeostasis that precedes pro-fibrotic events. Recent evidence suggests that innate immune cells reside in different tissues in a memory effector state, a phenomenon termed trained immunity, that may be activated by subsequent exogenous (e.g., microbial, dietary) or endogenous (e.g., metabolic, apoptotic) stmuli. This process leads to long-term modifications in the epigenetic landscape that ultimately precondition the cells towards enhanced transcription of inflammatory mediators that accelerates MAFLD development and/or progression. In this mini review we aimed to present current evidence on the potential impact of trained immunity on the pathophysiology of MAFLD, shedding light on the complex immunobiology of the disease and providing novel potential therapeutic strategies to restrain the burden of the disease.

What Are the Implications of COVID-19 on Breastfeeding? A Synthesis of Qualitative Evidence Studies.

INTRODUCTION: Exclusive breastfeeding until six months of life is the ideal way to feed infants. However, there is a significant number of infants who have never breastfed, despite the beneficial properties of breastfeeding. On the other hand, the coronavirus outbreak had significant effects on people's health, both mentally and physically, and has also impacted the breastfeeding process. AIM: The aim of this study was to investigate the implication of COVID-19 on breastfeeding through qualitative data from databases. METHODS: We searched online databases (PubMed, Google Scholar, PsycINFO) for studies published from 2019 to 2023. 'Out of the 2598 papers we found, only 12 were included in the review'. More specifically, from the 1558 papers remaining from the title and abstract evaluation as well as duplicates, a further 1546 papers belonging to our exclusion criteria were removed (all types of reviews, letters to editors, and quantitative articles). RESULTS: Our results covered three subjects: breastfeeding support during the pandemic, effects of social containment measures on breastfeeding, and additional outcomes regarding breastfeeding. Most voices found the effects of the pandemic on breastfeeding beneficial, with reduced professional support and a high degree of support from the environment. Additional negative factors were observed, as well as consequences of the pandemic in women's lives. CONCLUSIONS: COVID-19 was the occasion to understand the power of the supportive environment of the woman, especially the partner, in establishing and maintaining breastfeeding. Therefore, policy makers and health professionals, especially midwives, should implement family-centered breastfeeding strategies that are more supportive of the partner role, providing problem counseling when and where deemed necessary.